1. Field of the Invention
The present invention relates to pH dependent polymer micelles used for the encapsulation of hydrophobic organic compounds. The invention relates more specifically to the encapsulation of hydrophobic drugs in micelles for use in drug delivery.
2. Description of the Related Art
Micelles have been prepared by a wide variety of methods using an equally diverse group of compounds. Polymers have been used to form micelles for drug delivery. Such micelle forming polymeric drug formulations have generally been designed to behave in a pH independent manner and have comprised nonionic polymers or copolymers. E. Arca et al., Int. J. Polymer Analysis & Characterization (1995), 2, pp. 31-41; C. Ropert et al., Biochem. Biophys. Res. Commun. (1992), 187(2), pp. 379-885; K. Seki et al., Macromolecules (1984), 17, pp. 1692-1698; D. Collins and L. Huang in Molecular Mechanisms of Membrane Fusion (S. Ohki, D. Doyle, T. Flanagan, S. Hui and E. Mayhew, Eds; Plenum Press: N.Y. (1988), pp 149-161); D. Papahadjopoulos and A. Gabizon in Horizons in Membrane Biotechnology (C. Nicolau and D. Chapman, Eds; Wiley-Liss: N.Y. (1990), pp. 85-93); and G. S. Kwon and K. Kazunori, Adv. Drug Delivery Reviews (1995), 16, 295-309. The prior art polymers have generally been block copolymers.
The primary drawbacks of those methods has been lack of sufficient drug loading as well as lack of tissue targeting which is particularly important in the chemotherapeutic treatment of neoplasia related diseases such as cancer and tumors. Additionally, prior art formulations have not been based on pH sensitive poly(vinyl N-heterocycle) containing copolymers.
Even though various methods have been developed to deliver hydrophobic drugs, no single method has been found to be universally applicable and have a high success rate. Delivery of hydrophobic drugs resulting in increased bioavailability and/or preferred tissue targeting remains a problem to the pharmaceutical industry.
Accordingly, there is a need to develop more efficacious drug delivery methods for the delivery of hydrophobic drugs. Specifically, there is a need for formulations capable of forming stable micelles under a first physiological condition, such as high pH, and having the micelles disrupted under a second physiological conditions, such as low pH.
It is an object of the present invention to provide a formulation comprising the diblock copolymer poly(vinyl N-heterocycle)-block-poly(alkylene oxide) and a pharmacologically active compound, where the copolymer is capable of forming micelles in a pH dependent manner in an aqueous medium.
It is another object of the present invention to provide a formulation comprising a pharmacologically active compound and a poly(vinyl N-heterocycle)-block-poly(alkylene oxide) copolymer which will form micelles in a water containing medium when the copolymer is in an environment having a pH where the N-heterocycle nitrogen(s) is unprotonated.
It is yet another object of the present invention to provide a formulation comprising a pharmacologically active compound and a poly(vinyl N-heterocycle)-block-poly(alkylene oxide) copolymer which will form micelles when the N-heterocycle containing block is unprotonated and not form micelles when the N-heterocycle containing block is protonated. It is still yet another object of the present invention to provide a formulation comprising micelles which comprise a pharmacologically active compound and a poly(vinyl N-heterocycle)-block-poly(alkylene oxide) copolymer having pH dependent properties. Another object of the present invention to provide a micelle containing formulation wherein the micelle comprises a pharmacologically active compound and a poly(vinyl N-heterocycle)-block-poly(alkylene oxide) copolymer that forms micelles at higher than physiological pH values and does not form micelles at lower than physiological pH values.
It is a still further object of the present invention to provide a micelle containing pharmaceutical formulation, the micelle comprising a relatively hydrophobic therapeutic compound and a poly(vinyl pyridine)-block-poly(ethylene oxide) copolymer having pH dependent properties. A further object of the present invention to provide a micelle containing pharmaceutical formulation having pH dependent properties, the micelle comprising a relatively hydrophobic therapeutic compound, a poly(vinyl N-heterocycle) homopolymer and a poly(vinyl N-heterocycle)-block-poly(alkylene oxide) copolymer.